Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer.

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through ß2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

Dynamics of cell-type transition mediated by epigenetic modifications.

Maintaining tissue homeostasis requires appropriate regulation of stem cell differentiation. The Waddington landscape posits that gene circuits in a cell form a potential landscape of different cell types, wherein cells follow attractors of the probability landscape to develop into distinct cell types. However, how adult stem cells achieve a delicate balance between self-renewal and differentiation remains unclear. We propose that random inheritance of epigenetic states plays a pivotal role in stem cell differentiation and present a hybrid model of stem cell differentiation induced by epigenetic modifications. Our comprehensive model integrates gene regulation networks, epigenetic state inheritance, and cell regeneration, encompassing multi-scale dynamics ranging from transcription regulation to cell population. Through model simulations, we demonstrate that random inheritance of epigenetic states during cell divisions can spontaneously induce cell differentiation, dedifferentiation, and transdifferentiation. Furthermore, we investigate the influences of interfering with epigenetic modifications and introducing additional transcription factors on the probabilities of dedifferentiation and transdifferentiation, revealing the underlying mechanism of cell reprogramming. This in silico model provides valuable insights into the intricate mechanism governing stem cell differentiation and cell reprogramming and offers a promising path to enhance the field of regenerative medicine.

CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex.

Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5' untranslated region (5'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2 -terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

Prediction and Analysis of Tourist Management Strategy Based on the SEIR Model during the COVID-19 Period.

Tourism destinations are now facing a dilemma choice of controlling the epidemic or developing the economy. This paper takes Macao, a typical international tourist city, as an example to study the strategy of tourist source control during the COVID-19 period. According to the published epidemic data of Macao, this study has established an improved SEIR (Susceptible-Exposed-Infected-Recovered) model, formulated six control strategies against the current epidemic, and used the model above to simulate the time required for all confirmed cases to recover and discharge under different strategies. By taking into consideration the gross revenue of Macao's gambling industry from 2017 to 2019, the impact of different strategies on the economy is predicted and three control strategies are found to be feasible. This study shows that an effective way to break through the above dilemma is to design the tourist management strategy by screening the source of passengers and controlling the upper limit of capacity of destination. These findings provide a scientific basis for tourism destinations in formulating public policies. The improved SEIR model is more consistent with the actual conversion rule of patients in the current COVID-19 epidemic, and it can be applied to further public health related research.

Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients' specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST.

Long-term use of ceftriaxone sodium induced changes in gut microbiota and immune system.

Antibiotic administration, while facilitating clearance of targeted infections, also perturbs commensal microbial communities. Previous studies have all focused on the effects of short term use of antibiotics. Here, we focus on the effects of long term use of antibiotic on gut microbiota and immunity. BALB/c mice received saline or different doses of ceftriaxone sodium (100, 200 and 400 mg/mL) via daily gavage for 150 days. Alterations of fecal microbiota, small intestine histopathology, body weight, spleen index, serum IgG, mucus SIgA, IFN-γ/IL-4 ratio, CD4/CD8 ratio and CD4+CD25+ cells were evaluated. Long term ceftriaxone sodium administration resulted in gut microbiota dysbiosis, intestine histological lesions, growth inhibition, spleen index reducing. The immune defense ability reduced as serum IgG and mucus SIgA decreased significantly. Not only the immune defense, long term ceftriaxone administration also affected immune regulation. The IFN-γ/IL-4 and CD4/CD8 ratios increased, the CD4+CD25+ cells reduced on days 30 and 60 after ceftriaxone administration. However, after 90 days of ceftriaxone administration, the IFN-γ/IL-4, CD4/CD8 ratios and CD4+CD25+ cells restored, which indicated a new balance of immune regulation had been formed. Overall, these findings contribute to our understanding of long term antibiotic administration influencing gut microbiota and immunity.

Investigation of low-molecular weight organic acids and their spatiotemporal variation characteristics in Hongfeng Lake, China.

The identities and concentrations of low-molecular-weight organic acids (LMWOAs) were determined by ion chromatography throughout a 20-m water column in Hongfeng Lake, China. The spatiotemporal variations of LMWOAs and their contributions to dissolved organic matter (DOM) in a research period of 24 hr were also investigated. The results demonstrated that five LMWOAs (lactic, acetic, pyruvic, sorbic, oxalic acid) were detected, and their total concentration and proportion in DOC were 6.55 micromol/L and 7.47%. Their average levels were 2.50, 0.65, 2.35, 0.96 and 0.09 micromol/L, respectively. LMWOAs were higher during daytime (10:00-18:00 on Jun 13, 2008) than nighttime (21:00-6:00 the next morning), in particular 4.99 micromol/L high in the epilimnion (< or = 1 m water depth), reflecting the fact that direct import from terrigenous sources and photochemical production from humic materials were dominant during LMWOAs' origin and accumulation. The same factors caused LMWOAs to be 0.63 micromol/L in the epilimnion higher than in the hypolimnion. The rapid decrease of total organic acid (TOA) up until 18:00 mainly resulted from bio-uptake and mineralization in the hypolimnion (>1 m water depth). Pyruvic acid increased with time in the epilimnion and decreased in the hypolimnion, largely related to the two contrary processes of continuous degradation and synthesis of macromolecular organic matter during life materials' cycle mediated by organisms. Simultaneously, plankton behavior and thermal stratification played a pivotal role in LMWOAs' behavior in the water column, causing decreasing and increasing profiles. The distribution of LMWOAs represents an interesting resource for biogeochemical research of DOM in aquatic ecosystems.

Temporal and spatial variations of low-molecular-weight organic acids in Dianchi Lake, China.

Low-molecular-weight organic acids (LMWOAs) in eutrophic lake water of Dianchi, Southwestern China Plateau were investigated diurnally and vertically using ion chromatography. Two profiles (P1 and P2) were studied due to the difference of hydrochemical features. Lactic, formic, pyruvic and oxalic acid were detected as major components at P1 and P2 which were on average 7.98 and 6.53 micromol/L, respectively, corresponding to their proportions of 2.68% and 2.48% relative to DOC. Pyruvic acid was regarded as the uppermost species at P1 and P2, reaching up to 3.82 and 3.35 micromol/L and accounting for 47.9% and 51.3%, respectively, in individual TOA. Although humus were of biogenetic production at both sites, the significant negative correlation between diurnal variations of TOAs, fluorescence intensity (FI) of protein-like components and humic-like components at P1 indicated LMWOAs were greatly originated from bacterioplankton excretion and degradation. However, correlations between diurnal variations of humic-like FI and physicochemical parameters demonstrated algal origination of LMWOAs at P2. Although content of humus was high, TOA at P2 was 1.45 micromol/L lower than that at P1, due to the co-influence of more intense photo-oxidation and aggregation at P2. Therefore, TOAs exhibited quite opposite diurnal variation trends of increasing-decreasing and decreasing-increasing at P1 and P2, respectively. Except for impact of solar radiation, bacterial decomposition and assimilation rendered shifts of maximal LMWOAs along water column at P1. Covering with massive algae, UV rays penetrated shallower depth that LMWOAs assembled in surface layer water before 18:00 at P2 and represented decreasing profiles.

Characteristics and distribution of low molecular weight organic acids in the sediment porewaters in Bosten Lake, China.

The composition and vertical profiles of low molecular-weight organic acids (LMWOAs) and the contribution of them to dissolved organic matter (DOM) in sediment porewaters in Bosten Lake, Xinjiang, China were investigated. The results showed that total concentration of LMWOAs was up to 94.5 micromol/L and their proportion in DOM was 5.6%, suggesting that LMWOAs were important chemical components in DOM in lake sediment porewaters. Among the seven LMWOAs, pyruvic and acetic acid had the highest concentrations with 26.30 and 8.31 micromol/L, accounting for 51.4% and 14.92% of LMWOAs, respectively. Trifluoroacetic and sorbic acid had the lowest concentrations, indicating that the compositions of LMWOAs in relative reducing environments were largely different from those reported in glacier, atmosphere and soils. The concentrations of lactic, acetic, formic, sorbic and oxalic acid decreased with increasing depth, probably relating to stronger microbial activities in the initial stage of early diagenesis. Trifluoroacetic acid was mainly anthropogenic with its concentration, showing a diffusive trend from the surface to bottom sediments. The concentrations of lactic acid and nitrate generally showed a consistent profile. The increasing concentration of pyruvic acid in the vertical profile was just opposite to that of sulfate, revealing a significant negative relationship between them. Oxalic acid remained constant except for an obvious peak at 6 cm depth. The results indicated the diversities in sources and behaviors for various LMWOAs during early diagenesis in sediments.

Habitual physical activity reduces the risk of ischemic stroke: a case-control study in southern china.

BACKGROUND: To ascertain the relationship between habitual physical activity and the risk of ischemic stroke among the Chinese population. METHODS: A case-control study was conducted in Foshan, Guangdong Province, during 2007-2008. Information on physical activity exposure and lifestyle characteristics was obtained from 374 incident ischemic stroke patients and 464 hospital-based controls (mean age 66 years) using a validated and reliable questionnaire. Logistic regression analyses were performed to assess the association between physical activity levels and the ischemic stroke risk. RESULTS: The control subjects reported significantly longer duration of strenuous sports and moderate activity in recent daily life than the stroke patients. Increased engagements in such leisure time activities were associated with reduced risks of ischemic stroke after adjustment for confounding factors. A significant inverse dose-response relationship was also found for total physical activity exposure, with an adjusted odds ratio of 0.25 (95% confidence interval = 0.14-0.45) for older adults engaged in 22 or more metabolic equivalent task hours per week relative to those engaged in less than 10 metabolic equivalent task hours per week. CONCLUSIONS: The study provided evidence of an inverse association between habitual physical activity and the risk of ischemic stroke, which is important for the promotion and encouragement of leisure time exercise activities among elderly Chinese adults.

Soy consumption reduces risk of ischemic stroke: a case-control study in southern china.

BACKGROUND: Experimental studies have suggested that soybean products may protect against ischemic stroke, but only limited epidemiological evidence is available. OBJECTIVE: Our aim was to investigate the relationship between soy food consumption and the risk of ischemic stroke among the Chinese population. METHODS: A case-control study was conducted in southern China during 2007-2008. Soy food consumption, dietary intake and lifestyle information were obtained from 374 incident ischemic stroke patients and 464 hospital-based controls. Logistic regression analyses were performed to assess the association between soy food intake and the ischemic stroke risk. RESULTS: The mean weekly soy food intake was significantly lower (p = 0.001) among cases (89.9, SD = 239.3 g) than control subjects (267.7, SD = 426.1 g). Increased consumptions of dried soybean, tofu, soymilk and total soy foods were associated with reduced risks of ischemic stroke after adjusting for confounding factors. The corresponding adjusted odds ratios for the highest versus lowest level (<50 g) of intake were 0.20 (95% confidence interval = 0.09-0.48), 0.56 (0.36-0.89), 0.18 (0.06-0.51) and 0.23 (0.14-0.39), with significant dose-response relationships observed. CONCLUSION: The results provided evidence of inverse association between habitual soy food consumption and the risk of ischemic stroke for Chinese adults.

Tea consumption and ischemic stroke risk: a case-control study in southern China.

BACKGROUND AND PURPOSE: Although experimental studies have suggested that tea consumption may reduce the risk of ischemic stroke, available epidemiological evidence is equivocal, mainly due to the lack of accurate measurements on tea exposure. This study aims to ascertain the relationship between tea drinking and ischemic stroke risk. METHODS: A case-control study was conducted in southern China from 2007 to 2008. A total of 374 patients with incident ischemic stroke and 464 control subjects (mean age, 69 years) were recruited from 3 hospitals in Foshan. Information on frequency and duration of tea drinking, quantity of dried tea leaves, and types of tea consumed, together with habitual diet and lifestyle characteristics, was obtained from participants using a validated and reliable questionnaire. Logistic regression analyses were performed for tea consumption variables accounting for confounders that affect the ischemic stroke risk. RESULTS: A significant decrease in ischemic stroke risk was observed for drinking at least one cup of tea weekly (P=0.015) when compared with infrequent or nondrinkers, the risk reduction being largest by drinking one to 2 cups of green or oolong tea daily. Significant inverse dose-response relationships were also found for years of drinking and the amount of dried tea leaves brewed. The adjusted ORs for the highest level of consumption in terms of frequency of intake, duration of drinking, and average tea leaves brewed were 0.61 (95% CI, 0.40 to 0.94), 0.40 (95% CI, 0.25 to 0.64), and 0.27 (95% CI, 0.16 to 0.46), respectively. CONCLUSIONS: Long-term tea consumption is associated with reduced risk of ischemic stroke.

[Low molecular weight carboxylic acids in precipitation during the rainy season in the rural area of Anshun, West Guizhou Province].

40 rainwater samples were collected at Anshun from June 2007 to October 2007 and analysed in terms of pH values, electrical conductivity, major inorganic anions and soluble low molecular weight carboxylic acids. The results showed that pH of individual precipitation events ranged from 3.57-7.09 and the volume weight mean pH value was 4.57. The most abundant carboxylic acids were acetic (volume weight mean concentration 6.75 micromol x L(-1)) and formic (4.61 micromol x L(-1)) followed by oxalic (2.05 micromol x L(-1)). The concentration levels for these three species during summer especially June and July were comparatively high; it implied that organic acids in Anshun may came primarily from emissions from growing vegetations or products of the photochemical reactions of unsaturated hydrocarbons. Carboxylic acids were estimated to account for 32.2% to the free acidity in precipitation. The contribution was higher than in Guiyang rainwater, which indicated contamination by industry in Guiyang was more than in Anshun. The remarkable correlation(p = 0.01) between formic acid and acetic acid suggest that they have similar sources or similar intensity but different sources. And the remarkable correlation (p = 0.01) between and formic acid and oxalic acid showed that the precursors of oxalic acid and formic acid had similar sources. During this period, the overall wet deposition of carboxylic acids were 2.10 mmol/m2. And it appeared mainly in the summer, during which both concentration and contribution to free acidity were also relatively high. Consequently, it was necessary to control emission of organic acids in the summer to reduce frequence of acid rain in Anshun.

[Low-molecular-weight organic acids in precipitation in Zunyi City, Guizhou province].

Formic (HCOOH) and acetic (CH3COOH) acids are ubiquitous in troposphere. Studies on the low-molecular carboxylic acids help shed light on the biogeochemical cycles of carbon, hydrogen and oxygen, as well as on the formation of acid precipitation. As a city with severe acid precipitation, the city Zunyi in north Guizhou province, provide a typical background for gaining insight into the organic geochemistry in the heavily polluted atmospheric environment. We collected the precipitation in the downtown city for a whole year on the event basis, and measured inorganic and organic anions with ion chromatograph and cations with atomic absorption spectroscopy. The data demonstrate an annual average pH of 4.11, a clear indication of the acid atmosphere. The volume-weighted mean concentrations of [HCOO-]T and [CH3COO-]T were 9.29 micromol x L(-1) (ranged from 0.15 micromol x L(-1) to 46.14 micromol x L(-1)) and 6.47 micromol x L(-1) (ranged from 0.02 micromol x L(-1) to 19.11 micromol x L(-1)) respectively, accounting for 4.10% of the total anions. With a coefficient of 0.86, formic is significantly correlated with acetic acid, suggesting that both acids share common sources. The acids often decrease with time in a precipitation event, with occasional increases in the middle and last stages, indicating that the organic acids are primarily scavenged from blow cloud, with limited amount from the long distance transportation. The close range provenance of organic acids is facilitated by the local environmental condition, which is characterized by the mountain-enclosed valley with high humidity, low wind speed, and high atmospheric dust content. Based on the Henry's Law, we proposed the ratio of formic and acetic acids in the precipitation (F/A)aq as the indicator of the sources, and thus found that the anthropogenic sources are responsible for the organic compounds in the Spring and Winter, while vegetation emissions claim the sources in the Summer and Autumn.

[Seasonal variations of HCOOH and HCHO in precipitation in Guiyang].

Formic acid and formaldehyde are the important and ubiquitous chemical constituents in the atmosphere. Precipitation in Guiyang, the capital city of Guizhou province, was analyzed with ICS-90 ion chromatography for their concentration changes in a year. The volume mean weight average concentration (VMWA) is (13.27 +/- 25.92) micromol/L and (7.89 +/- 8.92) micromol/L for formic acid and formaldehyde, respectively. Both species demonstrated higher concentration during winter-half-year than the summer-half-year. Day-time concentration is higher than the night-time, the diurnal variations for both chemical constituents indicate the sources from human activities and photochemical reactions. Regression analysis of concentration vs precipitation volume and deposition amount vs precipitation volume reveals that dilution and scavenging of precipitation in the below-cloud process are responsible for the changes of the concentrations. The significant correlation between formic acid and formaldehyde suggests similar sources or reaction relationship. The known aqueous oxidation of formaldehyde, however, can not be used to explain the link of the two compounds, and thus should not be the major source of formic acid in Guiyang, Instead, photochemical reactions of unsaturated hydrocarbons (natural or anthropological) were the major sources for formic acid and formaldehyde.

Hospitalizations for incident stroke in Shunde District, Foshan, South China.

BACKGROUND/AIM: Stroke is a leading cause of mortality and morbidity in China. Accurate diagnosis of stroke type requires advanced imaging techniques. However, CT scan and MRI were not widely used in China until the middle 1990s. We estimate the stroke incidence based on stroke hospitalizations in Shunde District, Foshan, south China. METHODS: Stroke hospitalization rates were calculated for different age strata using the number of cases observed and the population size of Shunde in 2005 and 2006. RESULTS: The age-adjusted hospitalization rates (per 100,000 person-years) for all strokes were 57.4 overall, 65.1 for males and 50.0 for females, standardized according to Segi's world population. CONCLUSION: The stroke incidence appeared to be lower in Shunde than those reported for other parts of China.

The reliability of dietary and lifestyle information obtained from spouses in an elderly chinese population.

In many health studies of the elderly population, the subjects have cognitive or linguistic impairments, so data need to be collected from surrogates. This study compares dietary and lifestyle information reported by elderly Chinese with those provided by their spouses. Community couples 60 years and older were recruited to participate in an interview. One person from each couple was randomly chosen as the index person. Characteristics concerning the index person were then solicited from that person and separately from his or her spouse using validated questionnaires. For the 128 food items considered, the mean kappa was 0.73 for both frequency (SD 0.18) and amount (SD 0.22) of intake, and more than 70% of the couples had kappa statistics exceeding 0.61. Food items exhibiting high agreement between the spouses include rice, apples, tomatoes, and pork chops. The proportion of perfect agreement was higher than 80% for physical activity, smoking, and tea drinking behaviors. In conclusion, the spouse can serve as a proxy to provide reliable information when his or her partner is unavailable.